Page 154 - ebook HCC

GENEVA, SWITZERLANDA, SWITZERLAND
PROGRAMME AND ABSTRACTSAND ABSTRACTS
EASL HCC SUMMITHCC SUMMIT
152 PROGRAMME GENEV EASL 153
152
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FEBRUARY 13 - 16, 2014Y 13 - 16, 2014
FEBRUAR
Poster Board Number B41 Poster Board Number B42
CELL CYCLE DEREGULATION BY HCV PI3K/AKT PATHWAY ACTIVATION BY HCV AND
PROTEIN EXPRESSION, A POTENTIAL ITS ROLE IN LIVER CARCINOGENESIS
HEPATOCARCINOGENIC TRIGGER
Mohamed R. Imache , Jacqueline Polyte , Jean-Michel Pawlotsky , Herve Lerat 1
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1 Equipe 18, Université Paris Est - Inserm U955, Microbiology and Virology, Henri
Alexandre Florimond , Philippe Chouteau , Aurore Gaudin , Hervé Lerat , Mondor Hospital, Creteil, France
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Jean-Michel Pawlotsky on behalf of INSERM U955 EQ18 and INSERM U955,
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University of Paris-Est, Henri Mondor Hospital and National Reference Center for Viral
Hepatitis B, C, and Delta, Department of Virology Créteil, France Corresponding author’s e-mail: herve.lerat@inserm.fr
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1 INSERM U955 EQ18, University of Paris-Est, INSERM U955 EQ18, University of Paris-
Est, National Reference Center for Viral Hepatitis B, C, and Delta, Créteil, France
Introduction: The Pi3K-AKT pathway is a critical intracellular node regulating cell survival
Corresponding author’s e-mail: alexandre.florimond@inserm.fr and proliferation. Activation of the AKT-pathway has been reported in many cancers,
including HCC. Activation of this pathway by HCV is debated. We have shown that c-MYC
Introduction: Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset is overexpressed through an AKT-dependent mechanism in HCV-infected patients and
and progression of hepatocellular carcinoma (HCC), which appears to be principally related transgenic mice expressing all HCV proteins.
to chronic local inflammation and fibrosis. Nevertheless, in vitro studies have shown that HCV
proteins can directly interact with cell cycle regulators, tumour suppressors or oncogenes. Aims: This study aimed at characterizing AKT activation during HCV infection and
deciphering the underlying molecular mechanisms.
Aims: Our goal was to study the hepatocyte cell cycle perturbation(s) induced in vivo by
the expression of HCV proteins after an acute liver injury (CCl ) using a transgenic mouse Results: We observed a significant hyperphosphorylation of AKT-ser473 in non-tumoral
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model expressing the full HCV open reading frame (FL-N/35 mice).
BASIC POSTER ABSTRACTS Results: Early after the CCl challenge, no difference in the expression of immediate-early patients. This activation was also found in 3 months-old HCV transgenic mouse livers BASIC POSTER ABSTRACTS
hepatic tissues from infected patients with HCC as compared to HBV-infected or alcoholic
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genes, growth factors or cytokines was observed between the FL-N/35 mice and their
compared to wild-type, even after EGF treatment. AKT1, but not AKT2, was the activated
wild-type littermates (wt), suggesting that cell cycle initiation steps are not perturbed by
form. Our assessment of AKT phosphorylation modulators ruled out the involvement
HCV protein expression.
of phosphatases PP2A and PHLPP, but showed an increase in the phosphorylation of
In contrast, cyclin-A expression and BrdU incorporation at entry into the S-phase were
delayed in FL-N/35 mice compared to wt. At entry into the S-phase, Retinoblastoma
phosphorylation of Rictor-thr1135, p70S6K-thr389 and PDK1-ser241.
) was reduced in FL-N/35 mice, suggesting a
protein (Rb) phosphorylation (P-RB
Ser807/811
G1/S transition impairment in the liver of these mice. mTOR-ser2448 within the mTORC2 complex. This increase was associated with reduced
Chronic infection by HCV is associated with hepatic oxidative stress that could trigger Conclusions: Our results suggest that HCV protein expression modulates the negative
DNA damage, a well characterized cell cycle disruptor. As already published and as feedback loop that controls AKT phosphorylation, thus leading to its hyperactivation.
observed by ourselves, FL-N/35 mouse livers display high levels of Reactive Oxygen
Species (ROS) in association with an increased mitochondrial DNA damage. It has been The downstream effects of this HCV-induced Pi3K/AKT pathway activation and their
established that the ATM pathway is activated by DNA double-strand breaks and leads involvement in hepatic carcinogenesis are under study. Numerous molecules targeting the
to cell cycle arrest. We observed that Chk2 and p53 phosphorylations (Chk2 Thr68 and PI3K/AKT pathway have been tested in other cancers than HCC. Our results suggest such
p53 Ser15 ) and p21 waf1/cip1 expression, three actors of the ATM pathway, were significantly approaches could be valuable in the prevention or treatment of HCV-associated HCC.
higher in FL-N/35 mice than in wt mice at G1/S transition. Interestingly, these activations
were also present in untreated transgenic mice, indicating that such cell cycle brakes are
present independently of acute liver injury. Altogether, these results suggest that HCV-
induced DNA-damage impairs hepatocyte cell cycle G1/S transition, at least in part viathe
activation of the ATM pathway.

Conclusions: The expression of HCV proteins in the liver of HCV transgenic mice, in
the absence of detectable local inflammation or immune response, inhibits the G1/S
transition which could result of a HCV-induced DNA damage/ATM pathway activation.
This phenomenon represents a potential trigger of liver carcinogenesis.